|
|
Contents
|
Fever is mediated through production of prostaglandin E2 (PGE2) in the brain. To understand where and how PGE2 is produced in the brain, we have been studying expressions of enzymes responsible for PGE2 biosynthesis in the rat brain and its relevance to fever. In our typical experiment, rats were challenged with lipopolysaccharide (LPS, 0.1-0.4 mg/kg, i.p.). Five hours after the injection, their brain and cerebrospinal fluid were sampled for histological analysis and PGE2 assay, respectively, under diethyl ether or pentobarbital anaesthesia (5 mg/kg). In some cases, rats were pretreated with NS-398 (4 mg/kg, i.p.), an inhibitor of cyclooxygenase-2 (COX-2), prior to the LPS injection. The results were summarized as follows: (1) COX-2, an inducible-type enzyme converting arachidonic acid to PGH2, was induced in brain endothelial cells in response to LPS (Matsumura et al., 1998); (2) COX-2 expression was correlated with fever in terms of timing and magnitude (Cao et al., 1997); (3) Inhibition of COX-2 activity suppressed fever (Cao et al., 1997); (4) Microsomal-type PGE synthase (mPGES), another key enzyme that converts PGH2 to PGE2, was also induced in brain endothelial cells after LPS challenge; (5) mPGES was colocalized with COX-2 in the perinuclear region of the endothelial cells (Yamagata et al., 2001); (6) Inhibition of COX-2 activity suppressed PGE2 level in the brain; (7) Endothelial cells are the only cell group that expresses both COX-2 and mPGES in the brain; (8) Cytokine receptors are expressed in brain endothelial cells; (9) COX-2 induction and PGE2 elevation were not suppressed by bilateral vagotomy at the cervical level indicating that these responses are not vagally-mediated; and (10) Even under untreated conditions, low amounts of COX-2 and mPGES have been already expressed in brain endothelial cells. These results strongly suggest that circulating LPS and/or cytokines act on brain endothelial cells, which, in turn, produce PGE2 through inductions of COX-2 and mPGES. This seems to represent one of the humoral mechanisms of immune-brain communication that leads animals to fever.
Cao, C., Matsumura, K., Yamagata, K. and Watanabe, Y. (1997) Involvement of cyclooxygenase-2 in LPS-induced fever and regulation of its mRNA in the rat brain by LPS. Am. J. Physiol. 272:R1712-R1725.
Matsumura, K., Cao, C., Ozaki, M., Morii, H., Nakadate, K. and Watanabe, Y. (1998) Brain endothelial cells express cyclooxygenase-2 during lipopolysaccharide-induced fever: Light and electron microscopic immunocytochemical studies. J. Neurosci. 18:6279-6289.
Yamagata, K., Matsumura, K., Inoue, W., Shiraki, T., Suzuki, K., Yasuda, S., Sugiura, H., Cao, C., Watanabe, Y. and Kobayashi, S. (2001) Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever. J. Neurosci. 21:2669-2677.